Phenobarbital solubility in various binary and ternary propylene glycol-glycerol-water solvent systems was determined. Phenobarbital concentrations several times those of the ethanol-containing USP and BPC elixirs were obtained. From log solubility-solvent composition plots, a general equation was developed for phenobarbital solubility prediction in propylene glycol-water, glycerol-water, and propylene glycol-glycerol-water solvent systems. Solubility predictions using another equation, based on linear log solubility-dielectric constant relationships, were limited by the need to use different constants for different solvent blends. Heats of solution for phenobarbital determined in selected solvent blends as well as in USP and BPC elixirs varied within a very narrow range, suggesting similar solute-solvent interactions.